The ten-year (1993-2002) Baltimore Longitudinal Study of Aging prostate aging and disease study has both retrospective and prospective arms involving repeated assessments of anatomical, physiological, hormonal, and behavioral aspects of age-associated changes in prostate size. A major goal of the study is to identify antecedents of prostate cancer and benign prostatic hyperplasia (BPH). Current research is addressing the question of when serial measures of PSA are necessary, an interesting question because of the current controversy in medical practice about the clinical value of PSA. Over the past year, we have reported that there are safe levels of PSA that limit the need for further testing. We found that for PSA levels less than .5 for 60 to 65 year old men, no cases of cancer would be missed to age 75, an age where surgical treatment would be unlikely. Using this criteria would result in a 28% reduction in the number of men who would be unecessarily tested. If a level of 1.0 ng/ml were used 94% of cases would still be detected. If screening was stopped in 60 to 65 year old men with a PSA less than 1.0 ng/ml, there would be a 59 reduction in testing. These analyses argue that men can be clinically defined who are at low risk for the subsequent development of prostate cancer and where continued screening is unneccessary. We have demonstrated that normal levels of PSA can be used as a risk factor for the development of prostate cancer as long as 30 years prior to diagnosis in 40-50 year old men, and 15-20 years earlier in 50-60 year old men. The findings argue the potential to identify men at increased risk. We are now trying to identify the best strategy for the use of PSA in these men at increased risk. Furthermore, men who have a large prostate gland are at increased risk for the subsequent diagnosis of prostate cancer. What is unclear is whether the cancer is directly related to gland size, or if it is an artifact of both cancer and benign growth leading to elevated PSA levels. Currently, we are analyzing the impact of stratifying normal PSA levels in younger men on the size of their glands years later. We are finding that when 40 year old men are stratified by quartile of PSA, that those with a PSA above approximately 0.6 are at increased risk of having a large gland over the subsequent 25 years. Recent work has addressed the rate of growth of the prostate using longitudinal assessments by MRI. The overall rate of growth averaged 2.36 cc/year. The growth rate peaked in the 56 to 65 age range with an average growth of 4.15 cc/year, and then declined rapidly for older men. We have also examined whether serum selenium levels correlated with the risk of later development of prostate cancer using a case control design. Cases included 52 men in whom serum selenium was measured an average of 3.83 ? 1.85 years prior to diagnosis. These were compared to 96 age matched controls with no detectable prostatic disease. Serum selenium levels were found to decrease with increasing age. The risk of prostate cancer was lower in men with serum selenium levels above the lowest quartile with odds ratios of .29,.34, and .48 for subsequent quartiles (p=0.049). Age of the patients at diagnosis did not affect the protective effect observed for higher selenium values. The findings are consistent with other reports that higher serum selenium levels may be associated with a decreased risk of prostate cancer. At this point, we cannot address whether supplemental selenium may reduce the risk of prostate cancer. We have examined whether Insulin like growth factors (IGF's) play a role in prostate growth, hyperplasia and malignancy. High serum levels of IGF-I and low levels of IGF-II were found to be independently associated with increased risk of prostate cancer. However, PSA level is a much stronger predictor of the prostate cancer in the ensuing 10 years than either IGF-I or IGF-II. In addition, an absence of a relationship was found between IGF-I and prostate size suggesting that the increased risk of prostate cancer associated with higher IGF-I levels is not due to increased ascertainment in men with large prostates. The manuscript is currently in review.